The story begins on March 6, 2007 in a small town in New Hampshire called Sterling, tracking the lives of a number of characters on an ordinary day, including Alex Cormier, a superior court judge and her daughter, Josie, a junior in high school, Lacy and Peter Houghton, Detective Patrick Ducharme, Matt Royston (Josie's boyfriend) and several victims-to-be.

At the local high school - Sterling High, the story follows a routine day of students in classes, at the gym and in the cafeteria. Suddenly, a loud bang is heard from the parking lot, which turns out to be a bomb set off in Matt Royston's car. As the students are distracted by the noise, gun shots are fired. When Patrick, the only detective on the Sterling police force, arrives at Sterling High, he searches the school to seek out the gunman, who is allegedly reported to be a student. After passing dozens of dead and wounded victims, Patrick traps and captures the shooter in the locker room, in which he finds two kids (Josie and Matt) lying on the floor, surrounded in blood. Matt is dead and has two gunshots in his head and stomach (later he turns out to be the only dead victim to have been shot twice); Josie is not seriously injured, but shocked and cannot remember what happened.

The shooting killed ten people (nine students and one teacher) and wounded nineteen others.

Throughout the book, time flashes back and forth between events before and after the shooting. In the past, it is learned that Peter (the shooter) and Josie were once best friends. Peter was frequently the target of severe bullying at school, and Josie often stuck up for him. The friends slowly drifted apart as they got older; Josie joined the popular crowd out of her desire to become popular, and refused being Peter's friend any longer. The story also pictures Peter as an outcast at home; he had an older brother named Joey who Peter thought is favored by his parents. Joey was a popular straight-A student, athletic, and always ridiculed Peter, even fabricating a story to his friends that Peter was an adopted child. When Joey was killed in a car accident in 2006, the parents were too upset to pay attention to Peter, causing a bigger rift between Peter and his parents.

Josie began dating Matt in her sophomore year. Matt is a popular jock, who has always led his jock friends, mainly Drew Girard and John Eberhard, in bullying Peter. Matt often called Peter "homo" and "fag", leading Peter to question his own sexual orientation. The bullying got worse once Matt began dating Josie. He was a possessive and jealous boyfriend who admitted he did not like "sharing Josie" with others. On one occasion, Peter approached Josie after school to try talking to her, causing Matt to beat him up while Peter bled and cried in front of the school.

Readers also learn several sub-stories about the difficult relationship between Josie and her (single) mother, Alex's dilemma of being a judge and a mother, Peter's life as a constant bully bait and his escape to the computer world (e.g. video games), Josie's fear of falling out of the popular crowd and her suicide back-up plan when she does, Matt's abusive behavior toward Josie, Josie's pregnancy (and later miscarriage), Lewis Houghton hunting lessons with his son Peter.

One month before the shooting, after Peter realized he had feelings for Josie, he sent her an email expressing his love. Courtney Ignatio(Josie's friend and the first victim) read this email before Josie and had Drew forward it to the entire school. Courtney then convinced Peter that Josie did like him so Peter asks Josie to join him during lunch, only to suffer public humiliation as Matt pulls down Peter's pants and exposes his genitals in the cafeteria full of students.

After the shooting, Peter is sent to jail while the trial proceeds. The probable cause hearing is waived as Peter admits to killing ten people and wounding nineteen others. Jordan, the defense attorney, uses battered person syndrome (caused by severe bullying and abuse) as the basis to convince the jury that Peter’s actions were justified since Peter was suffering from post-traumatic stress disorder and was in a dissociative state at the time of the shooting. In the final stage of the trial, it is learned, out of Josie's confession as a witness, that she was the one who shot Matt first when she grabbed a gun falling out of Peter's bag that day, before Peter fired the second and fatal shot. Peter promised her he wouldn't tell, a promise which he keeps, because he was happy Josie had become his friend again. Josie admits that she shot Matt because she loved him and hated him at the same time. She hated herself for loving him, but if she didn't love him, she wasn't anybody anymore, and finally took a stand for herself after years of his abuse.

Peter is convicted of eight counts of first-degree murder and two counts of second-degree murder (manslaughter), which means he will be imprisoned for life. One month after his conviction, Peter commits suicide in prison.

At the end of the book, one year from the date of the massacre, Josie has received a five-year sentence for second-degree murder and is regularly visited in jail by her mother. Alex and Patrick are together and expecting their first child. Sterling High has been extensively remodeled. The cafeteria, the gym and locker room (where the massacre took place) have been replaced by a large glass atrium, with a memorial to the dead in the center, a row of ten white chairs bolted to the floor. A plaque declares the building "A Safe Harbor".

Post called the book not only a thriller that is "complete with dismaying carnage, urgent discoveries and 11th-hour revelations" , but also a source of serious moral questions about relationships between children and adult, and among children themselves.[7] The Boston Globe considered Nineteen Minutes "an insightful deconstruction of youthful alienation, of the shattering repercussions of bullying, and the disturbing effects of benign neglect."[8]